XRN2 Links Transcription Termination to DNA Damage and Replication Stress

Julio C. Morales, Patricia Richard, Praveen L. Patidar, Edward A. Motea, Tuyen T. Dang, James L. Manley, David A. Boothman

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

XRN2 is a 5’-3’ exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.

Original languageEnglish (US)
Article numbere1006107
JournalPLoS genetics
Volume12
Issue number7
DOIs
StatePublished - Jul 2016

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Morales, J. C., Richard, P., Patidar, P. L., Motea, E. A., Dang, T. T., Manley, J. L., & Boothman, D. A. (2016). XRN2 Links Transcription Termination to DNA Damage and Replication Stress. PLoS genetics, 12(7), [e1006107]. https://doi.org/10.1371/journal.pgen.1006107